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Zinc Deprivation Uncovers Vulnerabilities in Drug-Resistant Bacteria

Researchers at McMaster University have identified a significant vulnerability in drug-resistant bacteria related to zinc deficiency.

According to a recent study published in the journal Nature Microbiology, the role of zinc is critical in the resistance mechanisms of some of the most dangerous bacteria currently known.

Eric Brown, a professor in the Department of Biochemistry and Biomedical Sciences and the lead investigator of the study, highlights the importance of nutrient deprivation in altering the physiological state of bacteria, which can increase their susceptibility to antibiotics that they previously resisted.

“For a century, most research has focused on bacteria in nutrient-rich environments,” states Brown. “My lab has always been interested in the opposite approach: examining how nutrient scarcity impacts bacteria.”

This study aimed to investigate how nutrient stress could lead to novel strategies for combating infections resistant to critical antibiotics known as carbapenems.

“Carbapenems serve as last-resort antibiotics used when other treatments fail,” explains Megan Tu, a PhD candidate in Brown’s lab and the lead author of the paper. “However, the emergence of resistance genes threatens their effectiveness, and there are currently no clinically available solutions.”

To uncover new weaknesses in these resistant bacteria, the research team explored their behavior in environments that were low in zinc. They discovered that the bacteria’s resistance to carbapenems came with a significant “fitness cost,” indicating a trade-off.

Brown, also affiliated with McMaster’s Michael G. DeGroote Institute for Infectious Disease Research, provides a vivid analogy: envision a knight who must choose between wielding a sword and holding a shield.

“In this analogy, the knight represents the bacteria,” he elaborates. “When deprived of essential nutrients like zinc, the knight loses the capability to simultaneously wield both sword and shield, forcing it to abandon its shield to effectively use the sword.”

While the bacteria remain formidable, the loss of their defensive abilities exposes new vulnerabilities that can be targeted.

The researchers effectively capitalized on this newfound vulnerability.

Brown, Tu, and their colleagues demonstrated that by surviving carbapenem treatments in zinc-depleted environments, the bacteria became sensitive to azithromycin, one of the most frequently prescribed antibiotics worldwide.

“Instead of developing a new drug to combat antibiotic-resistant bacteria, we’ve unearthed a vulnerability that allows existing antibiotics to be repurposed,” Tu remarks.

Focusing on the bacteria Klebsiella pneumoniae and Pseudomonas aeruginosa, which are categorized as the ‘K’ and ‘P’ in the renowned ‘ESKAPE’ list of highly dangerous, drug-resistant pathogens, the study emphasizes significant findings.

Remarkably, both bacteria are classified as “gram-negatives,” which traditionally show resistance to azithromycin. This suggests that the findings could lead to new applications for established antibiotics, while reinforcing the concept of nutrient stress as a pathway to develop innovative treatments for drug-resistant bacterial infections.

“In our field, research often raises more questions than it answers—this is essential for driving progress,” Brown concludes. “However, this study stands out as a clear case where we confirm that azithromycin can indeed be used to treat specific drug-resistant infections caused by Kleb and Pseudomonas.

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